Alkanols inhibit voltage-gated K+ channels via a distinct gating modifying mechanism that prevents gate opening

摘要

Alkanols are small aliphatic compounds that inhibit voltage-gated K+ (K_v) channels through a yet unresolved gating mechanism. K_v channels detect changes in the membrane potential with their voltage-sensing domains (VSDs) that reorient and generate a transient gating current. Both 1-Butanol (1-BuOH) and 1-Hexanol (1-HeOH) inhibited the ionic currents of the Shaker K_v channel in a concentration dependent manner with an IC₅₀ value of approximately 50?mM and 3?mM, respectively. Using the non-conducting Shaker -W434F mutant, we found that both alkanols immobilized approximately 10% of the gating charge and accelerated the deactivating gating currents simultaneously with ionic current inhibition. Thus, alkanols prevent the final VSD movement(s) that is associated with channel gate opening. Applying 1-BuOH and 1-HeOH to the Shaker -P475A mutant, in which the final gating transition is isolated from earlier VSD movements, strengthened that neither alkanol affected the early VSD movements. Drug competition experiments showed that alkanols do not share the binding site of 4-aminopyridine, a drug that exerts a similar effect at the gating current level. Thus, alkanols inhibit Shaker -type K_v channels via a unique gating modifying mechanism that stabilizes the channel in its non-conducting activated state.